First Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China.
Experimental Center of Clinical College, The Hebei Medical University, Shijiazhuang City, Hebei Province, China.
Kaohsiung J Med Sci. 2022 Jan;38(1):38-48. doi: 10.1002/kjm2.12434. Epub 2021 Aug 9.
Proteins in Jumonji family function as histone demethylases and participate in cardiac development. Jumonji domain containing 5 (JMJD5) is responsible for the embryonic development through removing methyl moieties from H3K36me2 histone, and has pro-proliferative effect on heart and eye development. However, the protective role of JMJD5 against oxygen-glucose deprivation and reperfusion (OGD/R)-induced injury in cardiomyocytes has not been fully understood. Firstly, myocardial ischemia/reperfusion (I/R) rat model was established by ligation of left coronary artery. OGD/R was performed in non-transfected H9C2 or H9C2 transfected with pcDNA-JMJD5 plasmid to induce cell cytotoxicity. Data from qRT-PCR and western blot showed that JMJD5 was reduced in the heart tissues of myocardial I/R rat model and OGD/R-induced H9C2. Secondly, JMJD5 over-expression attenuated OGD/R-induced decrease in cell viability and increase in lactate dehydrogenase secretion and cell apoptosis in H9C2. Mitophagy was promoted by pcDNA-mediated over-expression of JMJD5 with enhanced protein expression of LC3-I, LC3-II, Atg5, and Beclin 1. Thirdly, knockdown of JMJD5 aggravated OGD/R-induced decrease in hypoxia-inducible factor-1α (HIF-1α), whereas JMJD5 over-expression enhanced BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein) through upregulation of HIF-1α. Lastly, BNIP3 silencing promoted cell apoptosis, suppressed mitophagy, and attenuated the protective effects of JMJD5 over-expression against OGD/R-induced injury in H9C2. In conclusion, JMJD5 exerted protective effects against OGD/R-induced injury in cardiomyocytes through upregulation of HIF-1α-BNIP3.
组蛋白去甲基化酶家族的蛋白质作为 JMJD5 参与心脏发育。JMJD5 通过去除 H3K36me2 组蛋白上的甲基基团，负责胚胎发育，并对心脏和眼睛发育具有促增殖作用。然而，JMJD5 在心肌细胞缺氧/葡萄糖剥夺再灌注（OGD/R）损伤中的保护作用尚未完全阐明。首先，通过结扎左冠状动脉建立心肌缺血/再灌注（I/R）大鼠模型。在未转染 H9C2 或转染 pcDNA-JMJD5 质粒的 H9C2 中进行 OGD/R，以诱导细胞毒性。qRT-PCR 和 Western blot 数据显示，JMJD5 在心肌 I/R 大鼠模型和 OGD/R 诱导的 H9C2 中的心脏组织中减少。其次，JMJD5 的过表达减弱了 OGD/R 诱导的 H9C2 细胞活力下降、乳酸脱氢酶分泌增加和细胞凋亡。通过 pcDNA 介导的 JMJD5 过表达促进了线粒体自噬，增强了 LC3-I、LC3-II、Atg5 和 Beclin 1 的蛋白表达。第三，JMJD5 的敲低加重了 OGD/R 诱导的缺氧诱导因子-1α（HIF-1α）减少，而 JMJD5 的过表达通过上调 HIF-1α 增强了 BNIP3（Bcl-2/腺病毒 E1B 19kDa 相互作用蛋白）。最后，BNIP3 沉默促进了细胞凋亡，抑制了线粒体自噬，并减弱了 JMJD5 过表达对 OGD/R 诱导的 H9C2 损伤的保护作用。总之，JMJD5 通过上调 HIF-1α-BNIP3 发挥对心肌细胞 OGD/R 损伤的保护作用。
